Adipose tissue has been recognized recently as a major metabolic and endocrine organ, in addition to its already known role as a fat reservoir and modulator of energy homeostasis. It has been proposed that impaired white adipose tissue (WAT) function, as well as decreased brown adipose tissue (BAT) activity or BAT mass, are main contributors to the development of obesity. In this regard, adipocyte and WAT dysfunction have been described in humans. Moreover, an inverse correlation between BAT activity and body mass index (BMI) has also been reported. See Yee J, et al., Lipids Health Dis. 2012, 11:19-30, Ichimura A, et al., Nature 2012; 483: 350-354, Mazzatti D, et al., Arch. Physiol. Biochem. 2012; 118(3): 112-120, Cypess A, et al., N. Engl. J. Med. 2009; 360:1509-1517, and van Marken Lichtenbelt W, et al., N. Engl. J. Med. 2009; 360:1500-1508.
The incidence of obesity has increased dramatically during the last decades to reach epidemic proportions. It is estimated that over 500 million individuals are obese. Obesity is a major public health problem today. See IASO, “Global Prevalence of Adult Obesity, Report IOTF 2008” (IASO, London, G B, 2009). Obesity per se increases the risk of mortality and has been long strongly associated with insulin resistance and type 2 diabetes. See Peeters A, et al., Ann. Intern. Med. 2003; 138:24-32 and Moller D, et al., N. Engl. J. Med. 1991; 325:938-948. In addition, adipocyte dysfunction and obesity are also significant risk factors for certain types of cancer and for many other serious illnesses such as heart disease, immune dysfunction, hypertension, arthritis, and neurodegenerative diseases. See Roberts D, et al., Annu. Rev. Med. 2010; 61:301-316, Spiegelman B, et al., J. Biol. Chem. 1993; 268(10):6823-6826, and Whitmer R, et al., Curr. Alzheimer Res. 2007; 4(2): 117-122.
Diet and exercise are the mainstay treatments for obesity, but an increasing number of patients also require pharmacotherapeutic intervention to decrease and maintain body weight. However, pharmacotherapy does not induce involuntary nor substantial weight loss and, additionally, anti-obesity drugs often display important side effects due to their systemic actions. Hence, there is an urgent need for novel and safe approaches to prevent and combat the current obesity epidemic. In this regard, unraveling the pathological events underpinning obesity is crucial for the development of new anti-obesity therapies. In vivo gene transfer of candidate genes to white and brown adipose tissue may offer great potential to gain insight into the molecular mechanisms underlying the onset and development of obesity. In addition, gene therapy approaches targeting adipocytes may open up new opportunities for the future treatment of obesity and their associated disorders while minimizing systemic effects. To date, however, effective and specific gene transfer to white and brown adipose tissue remains elusive.
Recently, the AAV of serotype 1 (AAV1) has been shown to modestly infect mouse WAT in vivo when combined with a non-ionic surfactant or celastrol. See Mizukami H, et al., Hum. Gene Ther. 2006; 17:921-928 and Zhang F, et al., Gene Ther. 2011; 18:128-134. Other AAV serotypes such as AAV6, AAV7, AAV8 or AAV9 have been reported to be highly infectious but their adipose transduction efficiency is unclear. See Gao G. et al., Proc. Natl. Acad. Sci. USA 2002; 99:11854-11859, Nakai H, et al., J. Virol. 2005; 79:214-224, Pacak C, et al., Circ. Res. 2006; 99:e3-e9, Broekman M, et al., Neuroscience 2006; 138:501-510, Wang Z, et al., Diabetes 2006; 55:875-884, Taymans J, et al., Hum. Gene Ther. 2007; 18:195-206, Bish L, et al., Hum. Gene Ther. 2008; 19:1359-1368, and Lebherz C, et al, J. Gene Med. 2008; 10:375-382. Thus, there is a need in the art for the development of vectors that allow the specific transduction of adipose tissue and, moreover, the transduction of particular types of adipose cells.